Case 2 DR IRENE SCHEIMBERG, CONSULTANT PAEDIATRIC & PERINATAL - - PowerPoint PPT Presentation

▶

May 15, 2023 519 likes •801 views

Case 2 DR IRENE SCHEIMBERG, CONSULTANT PAEDIATRIC & PERINATAL PATHOLOGIST THE ROYAL LONDON HOSPITAL, BARTS HEALTH NHS TRUST, LONDON, UK Clinical history Mother primigravida, high BMI Normal antenatal scans Reduced fetal movements

SLIDE 1

Case 2

DR IRENE SCHEIMBERG, CONSULTANT PAEDIATRIC & PERINATAL PATHOLOGIST THE ROYAL LONDON HOSPITAL, BARTS HEALTH NHS TRUST, LONDON, UK

SLIDE 2

Clinical history

 Mother primigravida, high BMI  Normal antenatal scans  Reduced fetal movements 48h before delivery at 40+4 weeks  Caesarean section due to profound & prolonged bradycardia  Male 4kg born in poor condition  HR 80bpm, spontaneous breathing at 6 minutes, O2 sats 80%  Cooling but he developed severe HIE  PPHN & diffuse cardiac hypertrophy  Intensive care withdrawn on day 2

SLIDE 3

Current case Range for GA Best fit Gestation 40 40 41 Birth weight 4002 2472-3372 2425-3625 Body weight 4213 2472-3372 2425-3626 Crown-heel 55.2 43.6-53.0 43.5- 53.3 Crown- rump 39 32.4-38.0 32.9-39.1 Toe-heel 8.5 6.9-8.5 7.1-8.7 Femur 7.9 7.2-7.8 7.2-7.9 Humerus 7 6.3-7.0 6.3-7.1 Head circ. 34 33-37 33.5-37.5 Weights in g; measurements in cm

Organs Current case Range for GA Range for BW Heart 32.5   14.8

21.1

31.9

Lung: BW

R. Lung

62.1

0.027
L. Lung

51.1

(combined)

113.2   21.9

67.3

84.6

N>0.015 for< 28wks Liver 136.2   92.1

163.7

148

N>0.012 for> 28wks Pancreas 6.0   2.3

3.1

Spleen 15.8   7.1

13.7

10.5

16.3

Brain: liver Thymus 6.0 4.5

14.5

7.8

15.2

2.7

R. Kidney

25.7

Normal = 3
L. Kidney

27.3

(combined)

53 15.8

38.8

24.9

45.1

Fetus: placenta Adrenals 8.0 4.7

10.7

6.7

14.1

NA Brain 368 277

357

Placenta NA   390

643
Weights in g

SLIDE 4

SLIDE 5

Heart

SLIDE 6

Histology coronary arteries

SLIDE 7

Carotid artery and branches

SLIDE 8

Infarct in papillary muscle

AV node

SLIDE 9

Lungs

SLIDE 10

SLIDE 11

Descending aorta and renal arteries

SLIDE 12

Adrenals and pancreas

SLIDE 13

Kidney and liver

SLIDE 14

Brain

CD68

SLIDE 15

Diagnosis

Generalized idiopathic arterial calcification of infancy (GACI)

SLIDE 16

GACI

 Rare autosomal recessive disorder  Diffuse calcification with hydroxyapatite deposits in the media’s elastic

lamina of large and medium sized arteries associated with intimal proliferation arterial stenosis

 Antenatal USS may show hydrops and calcification (from 18/40)  Depending on severity infants may present with IUD, NN heart failure,

arterial hypertension and death within the first 6 months of life in 60-80%

 Spontaneous regression and survival to adulthood  Biphosphonates (synthetic analogs of pyrophosphate) block

conversion of Ca+ into hydroxyapatite & calcifications disappear

 ENPP1 enzyme replacement therapy successful in mice (2018)

SLIDE 17

SLIDE 18

Genetics

 70%: Several inactivating mutations of the ENPP1

gene which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (PP1), a potent calcification inhibitor

 30%: inactivating mutations of ABCC6 gene

encoding an ATP-binding efflux transporter responsible for PXE (pseudoxanthoma elasticum)

 AR hypophosphatemic rickets may also be

associated with inactivation mutations of ENPP1 & may alleviate symptoms of GACI

SLIDE 19

GACI and PXE

 PXE: multisystemic ectopic mineralization disorder, late onset,

progressive clinical manifestations in skin, eyes and CV system

 Genotypic overlap between PXE and GACI  Several families with GACI have ABCC6 mutations. In one family one

sibling died of GACI and another develop PXE 25 years later

 Recent study: 92 GACI patients

 3 patients treated with biphosphonates presented later with clinical

features of PXE had ENPP1 mutations

 14 patients (of 28 with no disease causing ENPP1 mutation) had ABCC6

mutations

SLIDE 20

SLIDE 21

Mechanism of mineralization



ABCC6 mediates ATP release from hepatocytes to the extra cellular space where ATP is converted into Ppi and AMP by ENPP1



CD73 converts AMP to Pi & adenosine (inhibitor of tissue nonspecific alkaline phosphatase (TNAP) which hydrolyzes Ppi to Pi



Deficiencies in ABCC6, ENPP1 and CD73 lead to reduce plasma PPi levels and PPi/Pi ratios therefore promoting hydroxyapatite mineralization in peripheral tissues

SLIDE 22

Spectrum of the disease

SLIDE 23

SLIDE 24

SLIDE 25

Thank you

With thanks to Mo Haini

SLIDE 26

References



Chong CR, Hutchins GM. Idiopathic infantile arterial calcification:: The spectrum of clinical

presentations. Ped Develop Pathol 11:405:415; 2008



Mastrolia SA, Weintraub AY, Baron J et al. Antenatal diagnosis of idiopathic arterial calcification: a systematic review with a report of two cases. Arch Gynecol Obstet 291:977- 986; 2015



Nitschke Y, Baujat G, Botschen et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Med Gentics 90:25-39; 2012



Lorenz-Depiereux B, Schanbel D, Tiosano D, Hausler G, Strom TM. Loss of function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets. Am J Med Gentics 86:267-272; 2010



Uitto J, Li Q, van de Wetering K, Varadi A, Terry SF. Insights into pathomechanisms and treatment development in heritable ectopic mineralization disorders: summary of the PXE International Biennial Research Symposium-2016. J Invest Dermatol 137:790-795; 2017



Ali SA, Ng C, Votava-Smith JK, Randolph LM, Pitukcheewanont P. Biphosphonate therapy in an infant with generalized arterial calcification and ABCC6 mutation. Osteopor Int 2018, Sep 11 [Epub ahead of print]



Khan T, Sinkevicious KW, Vong S et al. ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification

f infancy (GACI). Dis Model Mech. 2018 Sep 3 [Epub ahead of print]